Biomarker Studies Could Realize Goal of More Effective and Personalized Cancer Medicine

When President Richard Nixon launched the war on cancer in his January 1971 State of the Union, he called for "the same kind of concentrated effort that split the atom and took man to the moon." Yet nearly 40 years and $100 billion in federally funded cancer research later, it seems the lunar landing was a much less daunting task.

Although much has been learned about the biology of cancer, the overall survival rate among people who have it has improved only slightly, according to a commentary published April 21 in Science Translational Medicine. The authors of the commentary argue that developing strategies to match new and existing drugs with the tumor characteristics of individual patients is a crucial step toward greater success in cancer treatment—an effort known as personalized medicine. "We have reached a juncture where talking about personalized cancer medicine and the importance of incorporating these goals into clinical trials is no longer sufficient," they wrote.

Biological and genomic studies are showing that most types of cancer are not single diseases, but rather complex disorders with distinct causes. Take breast cancer, for example: "When we say 'breast cancer', we're probably lumping 15 different diseases into that category," says co-author Joseph Nevins, director of the Duke Institute for Genome Sciences and Policy's Center for Applied Genomics & Technology. Subtle differences in the tumors' genomes and genetic expression are what make drugs work in certain patients and not in others. Yet most cancer drugs, with a few exceptions, are used with virtually no guidance as to which patients would benefit from them. "It is unrealistic to set goals of developing 'blockbuster' cancer drugs that are effective in all patients with a given disease," Nevins reports.

But it is no easy task to detect the subtle differences, or biomarkers, in those 15 types of breast cancer so that drugs can be targeted. "What we need are samples of the tumor to do more complex assays," Nevins says—assays that can detect genetic mutations and changes in gene-expression profiles. An example is the increased expression of the growth factor receptor HER2 in 20 percent of breast cancers. The test currently used to detect HER2 levels. was the subject of a recent New York Times article, in which a patient had a heterogeneous tumor with areas of both high and low expression. The concern was that herceptin, a drug that can treat roughly 30 percent of HER2-overexpressing tumors, has serious side effects and should therefore be avoided in patients without the HER2 abnormality. "I think the message from that is that it's a complex process we have to deal with. But the ability to enrich for patients that are likely to respond is far better than not using that test," Nevins says.

Although a biopsy is often collected to diagnose cancer, most clinical studies, including drug trials, don't re-collect samples before initiating treatment. But Nevins hopes this will change. "We're arguing that at this point in time we have to stop this process," he says. " Although we can't say that in each and every case the collection of biopsies will enable the development of effective biomarkers, we can say that in the absence of these tissue samples, biomarker development will be impossible."

Biomarker-development studies could enrich a study population with patients who are likely to respond to a given drug, which would increase the likelihood of clinical trials to generate more meaningful benefits. But collecting and analyzing the samples would also increase the workload within a trial significantly. "People worry that this would greatly slow the progress of clinical trials. But we're arguing that it doesn't do any good to do faster trials when we're not helping patients," Nevins says.

Time isn't the only limiting factor. It's expensive to collect tumor biopsies and perform these complex assays. But Nevins says the cost isn't a major concern, and it could be borne by funding agencies like the National Cancer Institute and even pharmaceutical companies running drug trials. "That's not the 'make or break'," he says. "The 'make or break' is to work this into a trial that can still recruit patients." Although mandatory biopsies might be seen as "too onerous," the authors say demonstrating the power of biomarker development to guide effective treatments will provide incentives for patients to go the extra step. A recent trial of personalized lung cancer treatment at the University of Texas M.D. Anderson Cancer Center enrolled 200 advanced-stage lung cancer patients and collected biopsies from each of them. Similarly, 377 breast cancer patients gave biopsies in a neoadjuvant breast cancer trial at the University of Medicine and Dentistry of New Jersey.

The idea of personalized medicine in cancer is not new. "Personalizing cancer care" was the theme for the American Society of Clinical Oncology's 2009 annual meeting, yet most of the studies presented there were performed in broad patient cohorts, the authors wrote. "Conducting trials that evaluate drugs in unselected populations of patients, knowing that only a very small fraction of these patients will actually benefit from the drug, is a practice that should stop," they wrote. "We owe it to the patients, and to all of us who potentially will be patients, to change this practice if we are to make meaningful gains in implementing effective cancer therapy and winning the war on cancer. "